Substituted 2 - (3 - aryl - 3 - keto (or 3-hydroxy)-propyl) - 1,2,3,4 - tetrahydroisoquinolines



United States Patent M US. Cl. 260-289 8 Claims ABSTRACT OF THE DISCLOSURE Pharmacologically active 2-[3-aryl-3-keto (or 3-hydroxy) propyl]-6,7 B-1,2,3,4-tetrahydroisoquinolines, wherein B is dialkoxy of alkylenedioxy, with or without position-1 substitution, are prepared from a 6,7-B-1,2,3, 4-tetrahydroisoquinoline, formaldehyde and a ketone of the formula R4 wherein R and R are lower alkyl or. together are trimethylene, tetramethylene or butadien-1,3)-ylene-(1,4), e.g., 3,4-dimethyl acetophenone, S-acetylindane, 2-acetyl naphthalene and Z-acetyl 5,6,7,8 tetrahydronaphthalene. The products are useful as antitussive and analgesic agents.

This invention relates, in general, to novel compounds and to a process for the production thereof. More particularly, the invention relates to tetrahydroisoquinoline compounds which have valuable phanmacological activity and to a method for producing same.

The novel compounds of this invention are tetrahydroisoquinoline compounds which have the general for- R R 4 I in which the symbol R represents hydrogen or a lower alkyl group; in which R represents a lower alkyl group; in which R represents .a lower alkyl group or, alternatively, in which R and R taken together, represent a methylene group; in which R represents a lower alkyl group; in which R represents a lower alkyl group or, alternatively, in which R and R taken together, represent a trimethylene, tetramethylene or butadien-(1,3)- ylene-(1,4) group; and in which A represents a carbonyl or hydroxymethylene group, and medicinally acceptable acid addition salts of the Formula I compounds.

The compounds of Formula I, and the acid addition salts thereof, have analgesic and antitussive activity and, hence, they are useful as analgesic agents and antitussive agents.

As used herein, the term lower alkyl denotes a straight chain or branched chain alkyl group containing from 1 to 8 carbon atoms. For example, the term lower alkyl embraces methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and isobutyl radicals. Exhibiting extremely interesting properties are the bases on Formula I, and the medicinally acceptable acid addition salts thereof, in which R represents hydrogen or a methyl group; in which R and R each represent a methyl group or in 3,450,704 Patented June 17, 1969 which R, and R taken together, represent a methylene group; and in which R and R each represents a methyl group or in which R, and R taken together represent a trimethylene, tetramethylene or butadien-(1,3)ylene- (1,4) group. Included among the compounds which are produced in the preferred practice of the invention are lmethyl-2 [3 (3 ,4-dimethylphenyl -3 -ketopropyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride;

11methyl-2- [3- (3 ,4-dimethylphenyl 3-ketopropyl] -6,7- methylenedioxy-l,2,3,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- [3 [indanyl- 5) ]3 -ketopropyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride;

2- [3 (3 ,4-dimethylpheny1) -3-ketopropyl] -6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- [3 [5,6,7,S-tetrahydronaphthyl- (2) 3-3ketopropyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- 3- [naphthyl- 2) ]-3-ketopropyl] -6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride;

2- [3-(3,4-dimethylphenyl)-3-ketopropyl]-6,7-methylenedioxy-l,2,3,4-tetrahydroisoquinoline hydrochloride;

1- methyl-2-[3-( 3,4-dimethylphenyl)-3-hydroxypropyl)- 6,7-dimeth0xy-1,2,3,4-tetrahydroisoquinoline hydrochloride;

l-methyl-Z- [3- 3,4-dimethylphenyl -3-hydroxypropy1] 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- [3- [indanyl-(S) ]-3-hydroxypropyl] -6,7-dimethoxyisoquinoline hydrochloride or hydroiodide;

l-methyl-Z- 3- 5,6,7, S-tetrahydronaphthyl- 2) ]-3-hydroxypropyl] -6,7-dimethoxy-1,2,3 ,4-tetrahydroisoquinoline hydrochloride;

1-methyl-2- [3 [naphthyl- (2) ]-3 -hydroxypropyl] -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline oxalate and 2- [3- (3 ,4-dimethylphenyl)-3 -hydroxypropyl] -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.

The compounds of Formula I, and the medicinally acceptable acid addition salts thereof, are readily prepared. In general, the preparative method involves reacting an amine having the formula Ii -O l R II in which the symbol R represents hydrogen or a lower alkyl group; in which R represents a lower alkyl group; in which R represents lower alkyl group; or, in the alternative, in which, taken together, R and R represent a methylene group, or an acid addition salt of such amine, with formaldehyde and a ketone having the formula R4 III in which R represents a lower alkyl group; and in which R represents a lower alkyl group; or, in the alternative, in which R and R taken together, represent a trimethylene, tetramethylene or butadien (1,3) ylene-(1,4)- group, by means of a Mannich reaction. In a subsequent step, the carbonyl compound which is produced can be reduced either catalytically or by treatment with an alkali-metal borohydride or an alkali-metal aluminum hydride. Where the amine of Formula II is provided in the form of the free base, the product, which is produced when it is reacted with formaldehyde and the ketone, is obtained as the free base. Where an acid addition salt of the amine is used as the starting material, the product is obtained as the salt. Similarly, the reduction product will be obtained as the free base or salt depending upon whetherthe reaction product which is reduced is in the form of the free base or the salt. In any event, the reaction product and the reduction product in the form of the free base can be converted into a salt or the salt converted into the free base by conventional procedures.

The amines of Formula II which are used as the starting material in the practice of this invention, and the acid addition salts of such amines, are known compounds. They can be obtained, for example, by reducing the corresponding 3,4-dihydroisoquinolines and, if desired, con verting the reduction product into an acid addition salt. The aforesaid 3,4-dihydroisoquinolines can be produced from the appropriate nuclear-substituted a-phenethyl amines by N-acylation and subsequent ring closures of the N-acylamine by means of the Bischler-Napieralski reaction. An interesting class of materials are the amines of Formula II, either in the form of the free base or an acid addition salt thereof, in which R represents hydrogen or a methyl group and in which R and R each represent a methyl group or, when taken together, R and R represent a methylene group.

The ketones of Formula III which are used in producing the products of this invention are also known compounds. They can be obtained, for example, by reacting a 3,4-di(lower alkyl)-benzene, indane, naphthalene or 5,6,7,8-tetrahydronaphthalene with acetyl chloride by means of a Friedel-Craft reaction. Among the more interesting ketone starting materials are 3,4-dimethyl acetophenone, S-acetyl indane, 2-acetyl naphthalene and 2- acetyl-5,6,7,8-tetrahydronaphthalene.

The Mannich reaction involving the amine of Formula II, either in the form of the free base or an acid addition salt, formaldehyde and the ketone of Formula III is carried out conveniently by heating the reactants in an inert organic solvent. Generally, the reactants will be heated for a period of from about three to about sixty hours. As the inert organic solvent, one can employ, for example, a lower alkanol, such as, ethanol. In the preferred embodiment of the invention, an acid addition salt of Formula II amine, particularly, a hydrohalide salt, such as, the hydrochloride, is employed. However, where an acid addition salt of the amine is used, it is generally advisable to incorporate into the reaction mixture also, a small amount of the acid corresponding to the acid portion of the salt used.

The catalytic reduction of those compounds of Formula I in which the symbol A represents a carbonyl group, or an acid addition salt thereof, is carried out conveniently in an inert organic solvent, such as a lower alkanol, for example, methanol, using hydrogen in the presence of a palladium or platinum catalyst. As the catalyst, there can be used, for example, palladium-on-carbon or platinum oxide. The reduction is carried out generally at room temperature and atmospheric pressure. In the alternative, the carbonyl compound of Formula I, i.e., the compound of Formula I in which the symbol A represents a carbonyl group, or an acid addition salt thereof, can be reduced by treatment with an alkali metal aluminum hydride or an alkali metal borohydride in an inert organic solvent. Where the reduction is carried out using an alkali-metal aluminum hydride, an anhydrous ether, such as diethyl ether or tetrahydrofuran, is employed as the inert organic solvent. Where the reduction is carried out using an alkali metal borohydride, a lower alkanol such as, methanol, ethanol, etc., or dioxan, or an aqueous solution thereof, is used as the solvent. In either event, the reduction is effected at a temperature of about 20 C. or lower. Where the reduction is carried out using an alkali metal aluminum hydride, lithium aluminum hydride is preferably employed. On the other hand, where the reduction is carried out using an alkali metal borohydride, sodium borohydride is preferably used.

Those compounds of Formula I in which the symbol A represents a carbonyl group and R represents a methyl group have an asymmetric carbon atoms and, hence, occur in the form of a stereoisomeric racemate. Those compounds of Formula I, in which the symbol A represents a hydroxymethylene group and R is a lower alkyl group, have two asymmetric carbon atoms and, hence occur in the form of two stereoisomeric racemates. Such racemates can, if desired, be separated into their optical isomers by conventional procedures. One such procedure involves the fractional crystallization of their salts.

As used herein, the expression medicinally acceptable acid addition salts connotes salts of the base with medicinally acceptable acids. Such acids may be inorganic or organic in nature and they include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, maleic acid, citric acid, oxalic acid, toluenesulfonic acid, etc.

As indicated heretofore, the novel tetrahydroisoquinoline compounds of Formula I, and the medicinally acceptable acid addition salts thereof, possess valuable pharmacological activity. Specifically, these compounds are useful as analgesic agents and as antitussive agents. The compounds can be used as medicaments in the form of pharmaceutical compositions suitable for enteral or parenteral administration. Thus, for example, the compounds of Formula I, including the medicinally acceptable acid addition salts thereof, can be provided as, and administered orally in the form of, tablets, pills, powders, capsules and granules. Additionally, the compounds can be provided as, and administered orally in the form of, emulsions, solutions, suspensions, etc. for oral administration. Furthermore, the compounds of the invention can be provided as, and administered parenterally in the form of, sterile aqueous suspensions, solutions or emulsions. Conventional procedures are utilized in producing the aforementioned dosage forms. The commonly used pharmaceutical adjuvants and/or excipients can be employed in preparing the various dosage forms. Such adjuvants and excipients include, for example, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, water, etc. The compounds of Formula I can be present in such preparations as the sole active ingredient thereof or they can be present therein in admixture with other therapeutically valuable substances.

The quantity of active medicament which is present in any of the above-described dosage forms is variable. It is preferred however, to provide capsules or tablets containing from about 5 mg. to about mg. of the Formula I base or an equivalent amount of a medicinally acceptable acid addition salt thereof. For parenteral administration, it is preferred to provide a solution containing from about 5 mg./ml. to about 11 mg./ml. of the Formula I base, or an equivalent quantity of a salt thereof. The frequency with which any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and requirements of the patient, as diagnosed by the prescribing physician. Under ordinary circumstances, however, up to about 8 mg/kg. of the compound can be administered daily in several dosages. It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this invention.

For a fuller understanding of the nature and objects of this invention, reference may be had to the following examples which are given merely as further illustration of the invention and are not to be construed in a limiting sense.

EXAMPLE 1 (a) In this example, a mixture of 22.2 grams (0.15 mol) of 3,4-dimethyl acetophenone, 36.6 grams (0.15 mol) of 1-methyl-6,7-dimethoxy l,2,3,4-tetrahydroisoquinoline hydrochloride and 6.75 grams of paraformaldehyde was added to a solution of 1 ml. of concentrated hydrochloric acid in 75 ml. of ethanol. This mixture was heated at its reflux temperature for a period of about twenty-four hours. At the end of that period of time the reaction mixture was cooled to a temperature of about C. The cream colored mass which was obtained was filtered and recrystallized from ethanol. There was thus obtained 1 methyl-Z-[3-(3,4-dimethylphenyl 3 ketopropyl] 6,7 dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in the form of white prisms having a melting point at 182 C. to 183 C.

(a) (i) By a procedure identical to that described in Section (a) of this example, using, however, 3,4-dimethyl acetophenone and l-methyl 6,7 methylenedioxy-1,2,3,4- tetrahydroisoquinoline hydrochloride as the ketone and amine reactants, respectively, there was obtained, after recrystallization of the product from ethanol, l-methyl-Z- [3-(3,4-dimethylphenyl)-3-ketopropyl] 6,7 methylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride, as pale yellow colored prisms of melting point 134 C.

(b) 0.02 mol of l-methyl-Z-[3-(3,4-dimethylphenyl)-3- ketopropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline, prepared from 8.5 grams (0.02 mol) of the hydrochloride salt produced as described in Section (a) of this example, was added to 100 ml. of dry ether and the solution was added, in a dropwise fashion at room temperature, to a stirred suspension of 1.15 grams (0.03 mol) of lithium aluminum hydride in 50 ml. of dry ether. When this addition was completed, the mixture was heated at its reflux temperature for a period of about four hours, following which it was cooled using an ice-water bath. Thereafter, the excess lithium aluminum hydride present in the reaction system was decomposed by the careful addition of ethyl acetate. The reaction mixture was then acidified with dilute sulphuric acid to form a two phase system. After the separation of the phases, the aqueous phase was made alkaline using a dilute sodium hydroxide solution and extracted twice with ether. The ether extracts were combined, washed with water and dried over sodium sulfate. The dried solution was filtered and the solvent was evaporated under reduced pressure. The oil which remained as the residue was taken up in ethanol and ethanolic hydrogen chloride was added thereto. After cooling, dry ether was added to the mixture. The product, thus formed, was obtained as a white solid. This product was recrystallized from an ethanol-ether mixture to yield l-methyl 2 [3 (3,4 dimethylphenyl)-3-hydroxypropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride in the form of white crystals melting at a temperature of about 99 C.

(b)(i) By a procedure, identical to that described in Section (b) of this example, using, however, as the starting material 1 methyl-2-[3-(3,4-dimethylphenyl)-3-ketopropyl] 6,7 methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride which was produced as described in Section (a) (i) of this example, there was prepared 1- methyl 2 [3,4-dimethylphenyl)-3-hydroxypropyl]-6,7- methylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride. The compound was obtained in the form of a white crystalline powder melting, after recrystallization from isopropanol-ether, at a temperature of about 165 C.

EXAMPLE 2 In this example, a mixture was prepared using 7.4 grams (0.05 mol) of 3,4dimethyl acetophenone, 11.51 grams (0.05 mol) of 6.7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride and 1.8 grams of paraformaldehyde in 25 ml. of ethanol. This mixture was heated at its reflux temperature for a period of about three hours. Thereafter, the mixture was cooled to a temperature of 0 C. whereupon there was deposited a solid product which wa recovered by filtration. This product was recrystallized from an isopropanol-ethanol-water mixture to yield 2-[3-(3,4- dimethylphenyl) 3 ketopropyl]-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline hydrochloride, melting at a temperature of about 225 C.

6 EXAMPLE 3 (a) In this example, a mixture of 32.0 grams (0.2 mol) of 5-acetyl indane, 48.8 grams (0.2 mol) of 1-methyl-6,7- dimethoxy 1,2,3,4-tetrahydroisoquinoline hydrochloride and 9.0 grams of paraformaldehyde in a solution of 0.5 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was first prepared. The mixture, thus obtained, was heated at its reflux temperature for a period of about sixteen hours. At the end of that period of time, the reaction mixture was cooled to about 0 C. Upon cooling a solid product was deposited from the reaction mixture which was recovered by filtration. The solid was thereafter recrystallized from ethanol to yield 1-methyl-2-[3-[indanyl-(5 )1- 3 ketopropyl] 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride melting at a temperature of from about189 C. to 191 C.

(b) (i) 12.5 grams (0.03 mol) of 1-methyl-2-[3-[indanyl (5 )]-3-ketopropyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, produced as described in Section (a) of this example were dissolved at room temperature in a mixture of 45 ml. of methanol and 25 m1. of 2-N sodium hydroxide solution. A solution of 1.2 grams (0.03 mol) of sodium borohydride in a mixture of 45 ml. of methanol and 6 ml. of 2-N sodium hydroxide solution was added thereto, in a dropwise fashion, over a period of about thirty minutes. The reaction mixture was then stirred for a period of about two and one-half hours, following which 200 ml. of water was added thereto. The reaction mixture was then extracted three times with ether. The ether extracts were combined, washed with water and dried over anhydrous sodium sulfate. The dried solution was filtered and the solvent was removed by evaporation. A colorless oil remained as the residue. This oil was dissolved in ethanol and ethanolic hydrogen chloride added thereto. Thereafter, the ethanol and ether were removed by evaporation and the oily residue which remained was dissolved in chloroform. The chloroform solution shaken for several minutes with an excess of an aqueous solution of potassium iodide. A two phase system developed. The chloroform layer was separated, washed once with brine and dried over anhydrous sodium sulphate. The dried solution was filtered and, subsequently, the solvent was removed by evaporation under reduced pressure. A yellowcolored gum-like product was obtained. Upon the addition of ether to that product, 1-methyl-2-[3-[indanyl-(S)]-3- hydroxypropyl] 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydroiodide was obtained in the form of a pale yellow, hygroscopic crystalline solid having a melting point at a temperature of C. to 98 C.

(b) (ii) In the paragraph which follows hereinafter there is described a reduction procedure leading to the hydrochloride salt of 1 methyl-2-[3-[indanyl-(5)]-3-hydroxypropyl] 6,7 dimethoxy-1,2,3,4-tetrahydroisoquinoline.

4.2 grams (0.01 mol) of 1-methyl-2-[3-[indanyl-(5)]- 3 ketopropyl] 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride produced as described in Section (a) of this example were dissolved in 100 ml. of ethanol. Thereafter, 0.15 grams of platinum oxide was added to the solution and the mixture was hydrogenated at room temperature and atmospheric pressure. The theoretical amount of hydrogen was taken up in a period of about eight hours. The mixture was then filtered, and the filtrate was evaporated to a volume of about 30 ml. Dry ether was then added to the solution and a white crystalline precipitate was obtained. This precipitate was recrystallized from an ethanol-ether mixture to yield 1-methyl-2- [3 [indanyl-(S)]-3-hydroxypropyl]-6,7-dimethoxy-1,2,3, 4 tetrahydroisoquinoline hydrochloride in the form of white microcrystals melting at a temperature of 108 C. to 110 C., with decomposition.

EXAMPLE 4 In this example, there was prepared a mixture of 17.4 grams (0.1 mol) of 2-acetyl-5,6,7,8-tetrahydronaphthalene,

24.4 grams (0.1 mol) of 1-methyl-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline hydrochloride and 4.5 grams of paraformaldehyde in solution of 0.5 ml. of concentrated hydrochloric acid in 50 ml. of ethanol. This mixture was heated at its reflux temperature for a period of about forty-eight hours. At the end of that period of time, the reaction mixture was cooled to a temperature of about C., whereupon there was deposited from the reaction mixture a solid which was removed by filtration. The solid product was then recrystallized from ethanol to yield 1- methyl 2 [3-[5,6,7,8-tetrahydronaphthyl-(2)]-3-ketopropyl] 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride melting at a temperature of 171 C. to 172 C.

4.3 grams (0.01 mol) of 1-methyl-2-[3-[5,6,7,8-tetrahydronaphthyl (2)] 3-ketopropyl] 6,7 dimethoxy- 1,2,3,4-tetrahydroisoquinoline hydrochloride, produced as described in the preceding paragraph, was suspended in 100 ml. of ethanol under nitrogen. To this suspension, 0.15 gram of platinum oxide (Adams catalyst) was added. The mixture was hydrogenated at room temperature and atmospheric pressure. After about four hours, the theoretical quantity of hydrogen, i.e., 270 ml., had been absorbed. The product which had formed was dissolved in the ethanol. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to a volume of about 30 ml. and cooled. Ether was added to the concentrate to cause the precipitation of a white solid product. The product was recrystallized from an ethanol-ether mixture to yield 1 methyl-2-[3-[5,6,7,8-tetrahydronaphthyl-(2) ]-3- hydroxypropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride in the form of white crystals melting at a temperature of 108 C. to 110 C.

EXAMPLE 5 In this example, a mixture of 25.5 grams (0.15 mol) of 2-acetyl naphthalene, 36.6 grams (0.15 mol) of l-methyl 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride and 6.75 grams of paraformaldehyde in a solution of 0.5 ml. of concentrated hydrochloric acid in 100 ml. of ethanol was first prepared. This mixture was heated at its reflux temperature for a period of about sixty hours. At the end of that period of time, the reaction mixture was cooled to a temperature of 0 C. whereupon there was deposited a solid product which was recovered by filtration. The product, so recovered, was recrystallized from an ethanol-ether mixture to yield 1-methyl-2-[3-naphthyl- (2)] 3 ketopropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride melting at a temperature of about 187 C.

6.4 grams (0.15 mol) of 1-methyl-2-[3-[naphthyl-(2)]- 3 ketopropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride, produced as described in the preceding paragraph, was dissolved in a mixture of 30 ml. of methanol and ml. of 2-N sodium hydroxide solution. While stirring, a solution of 0.6 gram (0.015 mol) of sodium borohydride in 10 ml. of methanol containing 3 ml. of dilute sodium hydroxide solution was added thereto in a dropwise fashion over a period of about thirty minutes. The reaction mixture, thus obtained, was stirred at room temperature for a period of about three hours, following which it was diluted with about 200 ml. of water and extracted two times with ether. The ether extracts were combined, washed with water and dried over anhydrous sodium sulfate. The dried solution was then filtered and evaporated under reduced pressure. A residual pale, yellow-colored, free flowing oil was obtained. This oil was treated with a methanolic solution of oxalic acid to yield 1 methyl 2 [3 [naphthyl (2)] 3 hydroxypropyl]- 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline oxalate, which after recrystallization from an ethanol-ether mixture, was obtained in the form of white crystals having a melting point at a temperature of 103 C.

EXAMPLE 6 In this example, a mixture of 6.0 grams (0.04 mol) of 3,4-dimethylacetophenone, 8.6 grams (0.04 mol) of 6,7- dimethylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride and 1.8 grams of paraformaldehyde in 25 ml. of ethanol was heated at its reflux temperature for a period of about two hundred and fifty-two minutes. At the end of that period of time, the reaction product was cooled to a temperature of 0 C. whereupon there was deposited a solid which, upon recrystallization from ethanol, yielded 2 [3 (3,4 dimethylphenyl) 3 ketopropyl] 6,7- methylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride having a melting point at a temperature of 212 C.

To a solution of 3.74 grams (0.01 mol) of 2-[3-(3,4- dimethylphenyl) 3 ketopropyl] 6,7 methylenedioxy- 1,2,3,4-tetrahydroisoquinoline hydrochloride in ml. of methanol there was added 0.3 gram of 5% palladiumon-charcoal catalyst. The mixture was hydrogenated at room temperature and atmospheric pressure. After sixteen hours the theoretical quantity of hydrogen had been absorbed. The catalyst was removed by filtration through diatomaceous earth which was then washed with methanol. The filtrate and washings were combined and evaporated to a volume of about 25 ml. Ether was added to the cooled solution and the white solid which formed was recrystallized from a methanol-ether mixture to yield 2- [3 (3,4 dimethylphenyl) 3 hydroxypropyl] 6,7- methylenedioxy 1,2,3,4 tetrahydroisoquinoline hydrochloride melting at a temperature of 199 C.

EXAMPLE 7 In the paragraphs which follow hereinafter, there is described illustrative methods for embodying the novel compounds of this invention in unit dosage forms.

(a) 15 grams of 1-methyl-2-[3-[indanyl-(S)]-3-ketopropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride, 102 grams of starch, 30 grams of hydrated silica and 3 grams of magnesium stearate were thoroughly mixed and the mass obtained was compressed into tablets, each such tablet weighing mg.

(b) 3 grams of 1-methyl-2-[3-(3,4-dimethylphenyl)-3- ketopropyl] 6,7 dimethoxy 1,2,3,4 tetrahydroisoquinoline hydrochloride, 44 grams of lactose, 48 grams of corn starch and 5 grams of talc were thoroughly mixed and the mass Obtained was compressed into tablets, each such tablet weighing 100 mg.

We claim:

1. A compound selected from the group consisting of a member having the formula in which R represents a member selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl; R represents a lower alkyl group; R represents a lower alkyl group and, taken with R a methylene group; R is selected from the group consisting of methyl, ethyl, propyl, and isopropyl; R is selected from the group consisting of methyl, ethyl, propyl, and isopropyl and, taken with R a member selected from the group consisting of trimethylene, tetramethylene and butadien-(1,3)-ylene- (1,4); and in which A represents a member selected from the group consisting of carbonyl and hydroxy methylene and a salt thereof with a medicinally acceptable acid.

2. A compound of claim 1 in which R is a member selected from the group consisting of hydrogen and methyl; R represents a methyl group; R represents a methyl group and, together with R a methylene group; R represents a methyl group; R represents a methyl group and, together with R a member selected from the 9 group consisting of trimethylene, tetramethylene and butadien- 1,3 )-ylene- (1,4).

3. The compound of claim 1 in which A is a carbonyl group; R is methyl; R is methyl; R is methyl; R is methyl and R is methyl.

4. The compound of claim 1 in which A is a carbonyl group; R is methyl; R is methyl; R is methyl; and R and R taken together, are a methylene group.

5. The compound of claim 1 in which A is a carbonyl group; R is methyl; R is methyl; R is methyl; and R and R taken together, are a trimethylene group.

6. The compound of claim 1 in which A is a hydroxymethylene group; R is methyl; R is methyl; R is methyl; R is methyl and R is methyl.

7. The compound of claim 1 in which A is a hydroxymethylene group; R is methyl; R is methyl; R is methyl; and R and R taken together, are a methylene group.

10 8. The compound of claim 1 in which A is a hydroxymethylene group; R is methyl; R is methyl; R is methyl; and R and R taken together, are a trimethylene group.

References Cited FOREIGN PATENTS 2/1965 Belgium. 7/1957 Austria.

10 ALEX MAZEL, Primary Examiner.

($3 3? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 53 5 Dated June 1'7, 1969 Inventor(s) John Mervyn Osband and Graham Alwyn Father-gill It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

r Calumn 1. line 18, "of" shtruld be Calumn 1, line 28, "butadien-Lj) shauld be:

butad1en-( 1. ,3) E

Calumn Q, line 56, "methyl-2%}, I

should be: y -I3(5,

Calumn 7, Tine 46, "l-methyl- 2-[3naphthyl" 1-meth 1-2-[5-[ naphbhyl- SIGNED RND SEALED MAY 1 21970 .Attest:

Edward M. Fletcher, Ir. WILLIAM E. S-GFRJYIIEIR. JR

Ancsting Officer Commissioner of Patents 

